Article abstract

Nature Chemical Biology 4, 498 - 506 (2008)
Published online: 11 July 2008 | Corrected online: 17 September 2008 | doi:10.1038/nchembio.100



There is a Corrigendum (October 2008) associated with this Article.

An integrated platform of genomic assays reveals small-molecule bioactivities

Shawn Hoon1,2, Andrew M Smith3,4,5, Iain M Wallace4, Sundari Suresh2, Molly Miranda2, Eula Fung2, Michael Proctor2, Kevan M Shokat6, Chao Zhang6, Ronald W Davis1,2, Guri Giaever3,5,7, Robert P St Onge2 & Corey Nislow3,4,5

Bioactive compounds are widely used to modulate protein function and can serve as important leads for drug development. Identifying the in vivo targets of these compounds remains a challenge. Using yeast, we integrated three genome-wide gene-dosage assays to measure the effect of small molecules in vivo. A single TAG microarray was used to resolve the fitness of strains derived from pools of (i) homozygous deletion mutants, (ii) heterozygous deletion mutants and (iii) genomic library transformants. We demonstrated, with eight diverse reference compounds, that integration of these three chemogenomic profiles improves the sensitivity and specificity of small-molecule target identification. We further dissected the mechanism of action of two protein phosphatase inhibitors and in the process developed a framework for the rational design of multidrug combinations to sensitize cells with specific genotypes more effectively. Finally, we applied this platform to 188 novel synthetic chemical compounds and identified both potential targets and structure-activity relationships.

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  1. Department of Genetics, Stanford University, Mail Stop-5120, Palo Alto, California 94305, USA.
  2. Stanford Genome Technology Center, 855 California Avenue, Palo Alto, California 94304, USA.
  3. Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada.
  4. Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, Ontario M5S3E1, Canada.
  5. Donnelly Centre for Cellular and Biomedical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada.
  6. Department of Molecular Pharmacology, University of California, 600 16th Street, MC 2280, San Francisco, California 94158-2280, USA.
  7. Department of Pharmaceutical Sciences, University of Toronto, 144 College Street, Toronto, Ontario M5S3M2, Canada.

Correspondence to: Robert P St Onge2 e-mail: bstonge@stanford.edu

Correspondence to: Corey Nislow3,4,5 e-mail: corey.nislow@utoronto.ca

* In the version of this article initially published, there was a space missing in the author name Robert P St Onge. The error has been corrected in the HTML and PDF versions of the article.

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